Angiogenesis is the process by which new blood vessels sprout from existing capillaries. This process plays an important role in such widely divergent biological conditions as embryonic development, tumor growth, wound healing, and chronic inflammatory diseases (Folkman et al., Science, 235, 442-447 (1987)).
Angiogenesis has received a great deal of attention recently because of the potential for manipulation to achieve therapeutic effects. For example, angiogenic processes may aid in the healing of wounds and fractures, the vascularizing of synthetic skin grafts, and the enhancement of collateral circulation where there has been vascular occlusion or stenosis.
Angiogenesis is also important for its detrimental effects in certain biological functions. For example, it is well known that tumor vascularization substantially contributes to the progression of cancer. Angiogenesis also plays an important role in diabetic retinopathy, Kaposi sarcoma, pannus formation in rheumatoid arthritis, and other diseases. The control of the angiogenic process, therefore, may be useful in new treatments for a variety of serious diseases.
Endothelial cells line the walls of blood vessels, and capillaries are comprised almost entirely of endothelial cells. The angiogenic process comprises a cascade of events, including protease secretion by endothelial cells, degradation of the basement membrane, migration through the surrounding matrix, proliferation, alignment, differentiation into tube-like structures, and synthesis of a new basement membrane (Furcht et al., Lab. Invest., 55, 505-509 (1986); Liotta et al., Cell, 64, 327-336 (1991)).
Several angiogenic agents with different properties and mechanisms of action are well known in the art. For example, acidic and basic fibroblast growth factor (FGF), transforming growth factor (TGF) alpha and beta, tumor necrosis factor (TNF), platelet-derived growth factor (PGDF), vascular endothelial cell growth factor (VEGF), and angiogenin are potent and well-characterized angiogenic agents. However, the therapeutic applicability of some of these compounds, especially as systemic agents, is limited by their potent pleiotropic effects on various cell types. There remains a need, therefore, for an angiogenic agent with more general applicability.